Organocatalytic one-pot synthesis of highly substituted pyridazines from morita-baylis-hillman carbonates and diazo compounds

Article abstract of DOI:10.1002/chem.201304295

A biologically inspired organocatalytic one-pot synthesis of highly functionalized pyridazines, which are ubiquitous structural units in a number of biologically active compounds, has been developed by starting from readily available diazo compounds and Morita-Baylis-Hillman (MBH) carbonates. Under mild reaction conditions, this synthetic route tolerated significant substrate variation to deliver a broad range of substituted products, including CF ₃-substituted pyridazines derivatives. Moreover, the introduction of trifluoromethyl groups into the ring of pyridazine could be completed conveniently from 2,2,2-trifluorodiazoethane. Go bio! A biologically inspired organocatalytic one-pot synthesis of highly functionalized pyridazines has been developed by starting from readily available diazo compounds and Morita-Baylis-Hillman (MBH) carbonates (see scheme; DABCO=1,4-diazobicyclo[2.2. 2]octane, Boc=tert-butoxycarbonyl). Under mild reaction conditions, this synthetic route tolerated significant substrate variation to deliver a broad range of substituted products, including CF₃-substituted pyridazines derivatives. Copyright

Full text of DOI:10.1002/chem.201304295

DOI: 10.1002/chem.201304295
Communication
&
Organic Chemistry
Organocatalytic One-Pot Synthesis of Highly Substituted
Pyridazines from Morita–Baylis–Hillman Carbonates and Diazo
Compounds
Haibin Mao,[a] Aijun Lin,[a] Zhongkai Tang,[a] Hongwen Hu,[a] Chengjian Zhu,*[a, b] and
Yixiang Cheng*[a]
Abstract: A biologically inspired organocatalytic one-pot
synthesis of highly functionalized pyridazines, which are
ubiquitous structural units in a number of biologically
active compounds, has been developed by starting from
readily available diazo compounds and Morita–Baylis–Hill-
man (MBH) carbonates. Under mild reaction conditions,
this synthetic route tolerated significant substrate varia-
tion to deliver a broad range of substituted products, in-
cluding CF3-substituted pyridazines derivatives. Moreover,
the introduction of trifluoromethyl groups into the ring of
pyridazine could be completed conveniently from 2,2,2-tri-
fluorodiazoethane.
Figure 1. Pyridazine-containing natural product and synthetic compounds.
Recently, the pyridazine core as a privileged structure[1] has at-
tracted more and more attention. Pyridazine-based scaffolds
are featured in a large number of natural products[2] and un-
natural compounds[3] with a broad range of biological and
pharmaceutical activities (Figure 1). Moreover, the modified
pyridazine structures are well-known ligands, which can coor-
dinate with some metals to afford organometallic complexes
with unique properties.[4] As a result, the effective synthesis of
structurally diverse pyridazine compounds is of considerable
significance.[5] Typically, the major synthetic routes (Scheme 1;
classification by the N sources of pyridazine) are as follows:
1) the addition of hydrazine or its derivatives to an appropri-
ately 1,4-disubstituted carbon chain,[6] 2) the inverse electron
Scheme 1. Methods for preparing pyridazine compounds.
demand cycloaddition of 1,2,4,5-tetrazine with alkenes and al-
kynes,[5a,7] 3) the addition of carbon-based nucleophiles to aryl
diazonium salts,[8] 4) the intramolecular diaza-Wittig reaction.[9]
thetic strategy, the functionalized pyridazines can be rapidly
The preparation of pyridazine compounds by the intramo-
lecular diaza-Wittig reaction is infrequent. However, by our syn-
synthesized under mild conditions. The main limitation of the
strategy is the development of direct and efficient methods to
construct the corresponding diazo precursors. As part of our
ongoing project on the synthesis of diazo compounds with
delicate functionalities,[10] herein, we report a convenient one-
pot synthetic route to construct highly substituted pyridazines
employing commercial diazo compounds and readily available
Morita–Baylis–Hillman (MBH) carbonates as reaction substrates.
We reasoned that a-allylic diazo compound A (Scheme 2)
could be obtained by the allylic alkylation of a-H diazo nucleo-
phile with MBH carbonate by a cascade SN2’–SN2’ process in
the presence of Lewis base (LB) catalyst.[10] After treatment
with phosphane, A would be reduced to the corresponding
[a] H. Mao,+ A. Lin,+ Z. Tang, Prof. Dr. H. Hu, Prof. Dr. C. Zhu, Prof. Dr. Y. Cheng
School of Chemistry and Chemical Engineering
State Key Laboratory of Coordination Chemistry
Nanjing University, Nanjing, 210093 (P. R. China)
E-mail: cjzhu@nju.edu.cn
[b] Prof. Dr. C. Zhu
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, Shanghai, 200032 (P. R. China)
[+] These authors contributed equally to this research.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304295.
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Table 1. Optimization of reaction conditions.[a]
Entry
LB
Phosphane
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
DMAP
Py
Et3N
DABCO
PPh3
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
P(nBu)3
P(nBu)3
P(nBu)3
P(nBu)3
P(nBu)3
P(Et)3
THF
THF
THF
THF
THF
THF
THF
THF
9
trace
trace
68
13
65
36
58
42
31
P(Cy)3
PPh(Et)2
P(nBu)3
P(nBu)3
P(nBu)3
P(nBu)3
9
DMF
10
11
12
CH3CN
1,4-dioxane
toluene
38
trace
[a] All reactions were performed in one pot. Reaction conditions: a) 1a
(0.2 mmol), 2a (2.0 equiv), Lewis base (0.1 equiv) in solvent (2.0 mL) at
room temperature (reaction was considered complete by TLC analysis);
b) the crude mixture was stirred with phosphane (3.0 equiv) under argon
atmosphere at room temperature for 3 h. [b] Isolated yield of 3a.
DMAP=4-dimethylaminopyridine.
Scheme 2. Organocatalytic one-pot synthesis of pyridazines from MBH car-
bonates and a-H diazo nucleophiles. Boc=tert-butoxycarbonyl.
iminophosphorane intermediate B (Scheme 2), which might
spontaneously undergo the intramolecular diaza-Wittig reac-
tion,[9] and then subsequent aromatization to give the pyrida-
zine scaffold.
employed as substrates, the transformation could be efficiently
completed in moderate-to-good yields (Table 2, 3h–p). The
ability to tolerate different halogen substituents (F, Cl, and Br)
into the corresponding products gave this process potential
for further synthetic transformations (Table 2, 3h–l). The MBH
carbonate bearing an electron-donating group (3o) was trans-
formed into the corresponding pyridazine product smoothly
with a longer reaction time. Notably, sterically demanding 1-
naphthyl and 2-naphthyl MBH carbonates were nicely convert-
ed into the desired adducts 3q in 57% yield and 3r in 54%
yield. The heteroaromatic MBH carbonates also smoothly cou-
pled with EDA to afford 4-(pyridin-2-yl)pyridazine 3s in 72%
yield and 4-(thiophen-2-yl)pyridazine 3t in 43% yield. In addi-
tion, the nonaromatic MBH carbonates could also successfully
undergo this one-pot process, giving 4-vinyl pyridazine 3x and
4-alkyl pyridazine 3y in moderate to good efficiency. Finally,
the uncommon MBH carbonates derived from alkyl vinyl ke-
tones and acrylamide were also investigated. In this case, 6-
alkyl pyridazine 3u–w were rapidly prepared, and 6-(phenyla-
mino)pyridazine 3z was obtained in 41% yield. Moreover, the
structure of 3i could be unequivocally assigned by X-ray dif-
fraction analysis.[11]
To demonstrate the feasibility of the proposed one-pot pro-
cess, a model reaction between ethyl diazoacetate (EDA, 1a)
and MBH carbonate 2a was performed in the presence of
10 mol% Lewis base at room temperature; and then the mix-
ture was treated with phosphane (Table 1). Examination of the
results of LB screening (Table 1, entries 1–5) revealed that only
1,4-diazobicyclo[2.2.2]octane (DABCO) (entry 4) exhibited re-
markable catalytic activity in an access to a-allylic diazo com-
pound. Different phosphanes were screened to convert the
diazo precursor into the pyridazine 3a in THF at room temper-
ature (entries 6–8 vs. 4). This effort led to the identification of
P(nBu)3 as the optimal phosphane, which provided the desired
pyridazine product in 68% yield. In addition, changing the sol-
vents to DMF, CH3CN, 1,4-dioxane, and toluene resulted in sig-
nificantly reduced yields (entries 9–12).
With the optimal reaction conditions in hand (DABCO
(0.1 equiv), P(nBu)3 (3.0 equiv), THF (2.0 mL), room tempera-
ture), we investigated the substrate scope of this one-pot reac-
tion (Table 2). Various diazo esters are suitable substrates lead-
ing to the desired products in 49–68% yields (Table 2, 3a–e).
The product 3c was obtained in lower yield compared with its
analogue 3a, which suggests that the bulky ester group is det-
rimental to the transformation. The MBH carbonates contain-
ing longer ester chain afforded 4-phenylpyridazine 3 f and 3g
in 61 and 53% yield, respectively. Remarkably, when a series of
MBH carbonates derived from substituted benzaldehydes were
Considering that fluorine-containing groups might signifi-
cantly modify the chemical and biological properties of organic
molecules,[12] and also upon consideration of the above pro-
posed mechanism (Scheme 2), we reasoned that this method-
ology might allow us to construct 6-(trifluoromethyl)pyridazine
scaffolds when employing 2,2,2-trifluorodiazoethane 4 as the
initial a-H diazo nucleophile. Gratifyingly, a clean transforma-
tion of 2,2,2-trifluorodiazoethane 4 and MBH carbonate 2a
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Communication
Table 2. Generality of the one-pot reaction of diazo esters.[a]
Table 3. Generality of the one-pot reaction of 2,2,2-trifluorodiazoethane
4.[a]
[a] All reactions were performed in one pot. Reaction conditions: a) 4
(0.42 molLÀ1 in THF, 0.47 mL), 2 (2.0 equiv), DABCO (0.1 equiv) in THF
(1.5 mL) at 08C (the reaction was considered complete by TLC analysis);
b) the crude mixture was stirred with P(nBu)3 (3.0 equiv) under an argon
atmosphere at room temperature for 3 h. Isolated yields of 5 are given.
zine compounds were synthesized and the results are summar-
ized in Table 3. Employing the MBH carbonates containing flu-
orine or trifluoromethyl groups as substrates provided an op-
portunity to procure polyfluorinated pyridazine compounds
(Table 3, 5b–c). Many different types of MBH carbonates bear-
ing aromatic fused ring, heteroaromatic ring, and alkyl moiet-
ies were transformed into the corresponding trifluoromethylat-
ed pyridazine derivatives 5d–h in 51–70% yields. The MBH car-
bonate derivative of methyl vinyl ketone was also efficiently
cyclized to give the product 5i in 68% yield.
To demonstrate the practical utility of our one-pot protocol,
the transformation was also performed on a large scale
(Scheme 3). When the reactions were conducted on a 6 mmol
scale, respectively, 1.07 g of 3a (65% yield) and 1.17 g of 5a
(73% yield) could be conveniently obtained.
[a] All reactions were performed in one pot. Reaction conditions: a) 1
(0.2 mmol), 2 (2.0 equiv), DABCO (0.1 equiv) in THF (2.0 mL) at room tem-
perature (reaction was considered complete by TLC analysis); b) the
crude mixture was stirred with P(nBu)3 (3.0 equiv) under an argon atmo-
sphere at room temperature for 3 h. Isolated yields of 3 are given.
In conclusion, we have developed a novel and efficient
method to construct highly functionalized pyridazines, which
are ubiquitous structural units in a number of biologically
active compounds. The combination of simple starting materi-
als under mild conditions (employing organocatalyst, without
metal catalyst and high reaction temperature) has been realiz-
into the corresponding a-allylic trifluorodiazoethane was ob-
served in the presence of DABCO (10 mol%) in THF at 08C.
After treatment of the above mixture with P(nBu)3 (3.0 equiv),
5-phenyl-6-(trifluoromethyl)pyridazine was isolated in 70%
yield (Table 3, 5a). Next, a variety of 6-(trifluoromethyl)pyrida-
Chem. Eur. J. 2014, 20, 2454 – 2458
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Communication
Acknowledgements
We gratefully acknowledge the
National Natural Science Foun-
dation of China (21372114,
21172106, 21074054), National
Science Fund for Talent Training
in Basic Science (no. J1103310),
the National Basic Research Pro-
gram of China (2010CB923303)
and the Research Fund for
the
Doctoral
Program
of
Higher Education of China
(20120091110010) for their finan-
cial support.
Scheme 3. Gram-scale experiment.
ed through allylic alkylation and intramolecular diaza-Wittig
processes. This one-pot synthetic route tolerated significant
substrate variation to deliver a broad range of substituted
products. Moreover, the introduction of trifluoromethyl groups
into the ring of pyridazine could be completed conveniently
from 2,2,2-trifluorodiazoethan. We believe that the strategy
demonstrated here may be of wide application in organic and
medicinal chemistry.
Keywords: diazo
carbonates · one-pot synthesis · organocatalysis · pyridazines
compounds
·
Morita–Baylis–Hillman
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Experimental Section
General procedure for the one-pot synthesis of highly sub-
stituted pyridazines 3 from MBH carbonates 2 and diazo
ester 1
The diazo ester 1a (22.8 mg, 0.2 mmol) was added to a stirring so-
lution of DABCO (2.3 mg, 0.02 mmol) and MBH carbonate 2a
(116.9 mg, 0.4 mmol) in anhydrous THF (2.0 mL) at room tempera-
ture. The reaction was monitored by TLC analysis. After the first
step, the reaction was considered completed and the mixture was
stirred with P(nBu)3 (121.3 mg, 0.60 mmol) under an argon atmo-
sphere at room temperature for 3 h. After evaporation of the sol-
vent under reduced pressure, the crude reaction mixture was di-
rectly purified by flash chromatography on silica gel (PE/EA=5:1)
to afford the corresponding product 3a (37.0 mg, 68% yield).
General procedure for the one-pot synthesis of 6-(trifluoro-
methyl)pyridazines 5 from MBH carbonates 2 and 2,2,2-tri-
fluorodiazoethane 4
The 2,2,2-trifluorodiazoethane 4 (0.42 molLÀ1 in THF, 0.47 mL,
0.2 mmol) was added to a stirring solution of DABCO (2.3 mg,
0.02 mmol) and MBH carbonate 2a (116.9 mg, 0.4 mmol) in anhy-
drous THF (1.5 mL) at 08C. The reaction was monitored by TLC
analysis. After the first step the reaction was considered complete
and the mixture was stirred with P(nBu)3 (121.3 mg, 0.60 mmol)
under an argon atmosphere at room temperature for 3 h. After
evaporation of the solvent under reduced pressure, the crude reac-
tion mixture was directly purified by flash chromatography on
silica gel (PE/EA=8:1) to afford the corresponding product 5a
(37.5 mg, 70% yield).
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[11] CCDC-963683 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Received: November 2, 2013
Published online on February 2, 2014
Chem. Eur. J. 2014, 20, 2454 – 2458
www.chemeurj.org
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